tbuckley/cabot-search huggingface dataset:
Involvement of Transcriptional Factor Pbx1 in Peripheral B Cell Homeostasis to Constrain Lupus Autoimmunity
Authors: Shuangshuang Gu, Jinsong Zhang, Xiaxia Han, Huihua Ding, Chao Yao, Zhizhong Ye, Zhihua Yin, Guojun Hou, Yang Jiang, Jie Qian, Haibo Zhou, Qiang Guo, Sheng Chen, Dai Dai, Nan Shen
Journal: Arthritis & Rheumatology (2023)

Disruption of B cell homeostasis and subsequent dominance of effector B cell subsets are critical for the development of systemic lupus erythematosus (SLE). Revealing the key intrinsic regulators involved in the homeostatic control of B cells has important therapeutic value for SLE. This study was undertaken to determine the regulatory role of the transcription factor Pbx1 in B cell homeostasis and lupus pathogenesis.We constructed mice with B cell-specific deletion of Pbx1. T cell-dependent and T cell-independent humoral responses were induced by intraperitoneal injection of nitrophenyl-containing hapten (NP) conjugated to keyhole limpet hemocyanin or NP-Ficoll. The regulatory effects of Pbx1 on autoimmunity were observed in a Bm12-induced lupus murine model. We investigated mechanisms of Pbx1 using RNA sequencing, the cleavage under targets and tagmentation assay, and chromatin immunoprecipitation-quantitative polymerase chain reaction assay. We transduced B cells from SLE patients with plasmids that overexpressed PBX1 to explore the in vitro therapeutic efficacy of PBX1.Pbx1 was specifically down-regulated in autoimmune B cells and negatively correlated with disease activity. The deficiency of Pbx1 in B cells resulted in excessive humoral responses following immunization. In the Bm12-induced lupus model, mice with B cell-specific Pbx1 deficiency displayed enhancements in germinal center responses, plasma cell differentiation, and autoantibody production. Pbx1-deficient B cells had increased survival and proliferative advantages after activation. Pbx1 regulated genetic programs by directly targeting critical components of the proliferation and apoptosis pathways. In SLE patients, PBX1 expression was negatively correlated with effector B cell expansion; when PBX1 expression was enforced, the survival and proliferative capacity of SLE B cells were attenuated.Our study reveals the regulatory function and mechanism of Pbx1 in adjusting B cell homeostasis and highlights Pbx1 as a therapeutic target in SLE.
Reduction of Neutrophil Activation by Phosphodiesterase 4 Blockade in Behçet's Disease
Authors: Alexandre Le Joncour, Paul Régnier, Anna Maciejewski‐Duval, Erwan Charles, Stéphane Barete, Pierre Fouret, Michelle Rosenzwajg, David Klatzmann, Patrice Cacoub, David Saadoun
Journal: Arthritis & Rheumatology (2023)

Objective Behçet's disease (BD) is a systemic vasculitis with inflammatory lesions mediated by cytotoxic T cells and neutrophils. Apremilast, an orally available small‐molecule drug that selectively inhibits phosphodiesterase 4 (PDE4), has been recently approved for the treatment of BD. We aimed to investigate the effect of PDE4 inhibition on neutrophil activation in BD. Methods We studied surface markers and reactive oxygen species (ROS) production by flow cytometry, and neutrophil extracellular traps (NETs) production and molecular signature of neutrophils by transcriptome analysis before and after PDE4 inhibition. Results Activation surface markers (CD64, CD66b, CD11b, and CD11c), ROS production, and NETosis were up‐regulated in BD patient neutrophils compared to healthy donor neutrophils. Transcriptome analysis revealed 1,021 significantly dysregulated neutrophil genes between BD patients and healthy donors. Among dysregulated genes, we found a substantial enrichment for pathways linked to innate immunity, intracellular signaling, and chemotaxis in BD. Skin lesions of BD patients showed increased infiltration of neutrophils that colocalized with PDE4. Inhibition of PDE4 by apremilast strongly inhibited neutrophil surface activation markers as well as ROS production, NETosis, and genes and pathways related to innate immunity, intracellular signaling, and chemotaxis. Conclusion We highlight key biologic effects of apremilast on neutrophils in BD.
Active Surveillance for Low-risk Papillary Thyroid Carcinoma
Authors: Shijie Yang, Meijuan Tan, Xiequn Xu
Journal: JAMA Oncology (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Association of Recent Violence Encounters With Suicidal Ideation Among Adolescents With Depression
Authors: Jing Wang, Shannon Harrer, Marissa L. Zwald, Ruth W. Leemis, Kristin M. Holland, Deborah M. Stone, Kathleen McDavid Harrison, Elizabeth A. Swedo
Journal: JAMA Network Open (2023)

Importance Suicide prevention is an important component of depression management. Knowledge about depressed adolescents with increased risk for suicide can inform suicide prevention efforts. Objective To describe the risk of documented suicidal ideation within a year following a diagnosis of depression and to examine how the risk of documented suicidal ideation differed by recent violence encounter status among adolescents with new depression diagnoses. Design, Setting, and Participants Retrospective cohort study in clinical settings including outpatient facilities, emergency departments, and hospitals. Using IBM’s Explorys database containing electronic health records from 26 US health care networks, this study observed a cohort of adolescents with new depression diagnoses from 2017 to 2018 for up to 1 year. Data were analyzed from July 2020 to July 2021. Exposures Recent violence encounter was defined by a diagnosis of child maltreatment (physical, sexual, or psychological abuse or neglect) or physical assault within 1 year before depression diagnosis. Main Outcomes and Measures The main outcome was diagnosis of suicidal ideation within 1 year following depression diagnosis. Multivariable adjusted risk ratios of suicidal ideation were calculated for overall recent violence encounters and for individual forms of violence. Results Among a total of 24 047 adolescents with depression, 16 106 (67.0%) were female and 13 437 (55.9%) were White. A total of 378 had experienceda violence (hereafter, encounter group) and 23 669 had not (hereafter, nonencounter group). Following the diagnosis of depression, 104 adolescents with any past-year violence encounter (27.5%) documented suicidal ideation within 1 year. In contrast, 3185 adolescents in the nonencounter group (13.5%) experienced thoughts of suicide following the diagnosis of depression. In multivariable analyses, those with any violence encounter had 1.7 times (95% CI 1.4–2.0) higher risk of documented suicidal ideation compared with those in the nonencounter group ( P &amp;amp;lt; .001). Among different forms of violence, sexual abuse (risk ratio, 2.1; 95% CI, 1.6–2.8) and physical assault (risk ratio, 1.7; 95% CI, 1.3–2.2) were associated with significantly increased risk of suicidal ideation. Conclusions and Relevance Among adolescents with depression, persons who experienced past-year violence encounters showed a higher rate of suicidal ideation than those who had not. These findings highlight the importance of identifying and accounting for past violence encounters when treating adolescents with depression to reduce risk of suicide. Public health approaches to prevent violence may help to avert morbidity associated with depression and suicidal ideation.
MSC-derived extracellular vesicles as nanotherapeutics for promoting aged liver regeneration
Authors: Jiebin Zhang, Tongyu Lu, Jiaqi Xiao, Cong Du, Haitian Chen, Rong Li, Xin Sui, Zihao Pan, Cuicui Xiao, Xuegang Zhao, Jia Yao, Yasong Liu, Yunguo Lei, Ying Ruan, Jian Zhang, Hua Li, Qi Zhang, Yingcai Zhang, Jianye Cai, Yang Yang, Jun Zheng
Journal: Journal of Controlled Release (2023)
Alcohol-induced extracellular ASC specks perpetuate liver inflammation and damage in alcohol-associated hepatitis even after alcohol cessation
Authors: Marcelle de Carvalho Ribeiro, Arvin Iracheta-Vellve, Mrigya Babuta, Charles D. Calenda, Christopher Copeland, Yuan Zhuang, Patrick P. Lowe, Danielle Hawryluk, Donna Catalano, Yeonhee Cho, Bruce Barton, Srinivasan Dasarathy, Craig McClain, Arthur J. McCullough, Mack C. Mitchell, Laura E. Nagy, Svetlana Radaeva, Egil Lien, Douglas T. Golenbock, Gyongyi Szabo
Journal: Hepatology (2023)

Background &amp; Aims: Prolonged systemic inflammation contributes to poor clinical outcomes in severe alcohol-associated hepatitis (AH) even after the cessation of alcohol use. However, mechanisms leading to this persistent inflammation remain to be understood. Approach &amp; Results: We show that while chronic alcohol induces nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation in the liver, alcohol binge results not only in NLRP3 inflammasome activation but also in increased circulating extracellular apoptosis-associated speck-like protein containing a caspase recruitment domain (ex-ASC) specks and hepatic ASC aggregates both in patients with AH and in mouse models of AH. These ex-ASC specks persist in circulation even after the cessation of alcohol use. Administration of alcohol-induced–ex-ASC specks in vivo in alcohol-naive mice results in sustained inflammation in the liver and circulation and causes liver damage. Consistent with the key role of ex-ASC specks in mediating liver injury and inflammation, alcohol binge failed to induce liver damage or IL-1β release in ASC-deficient mice. Our data show that alcohol induces ex-ASC specks in liver macrophages and hepatocytes, and these ex-ASC specks can trigger IL-1β release in alcohol-naive monocytes, a process that can be prevented by the NLRP3 inhibitor, MCC950. In vivo administration of MCC950 reduced hepatic and ex-ASC specks, caspase-1 activation, IL-1β production, and steatohepatitis in a murine model of AH. Conclusions: Our study demonstrates the central role of NLRP3 and ASC in alcohol-induced liver inflammation and unravels the critical role of ex-ASC specks in the propagation of systemic and liver inflammation in AH. Our data also identify NLRP3 as a potential therapeutic target in AH.
Oxysterol metabolism dictates macrophage influx during SARS-CoV-2 infection
Authors: Thomas M. Conlon, Ali Önder Yildirim
Journal: European Respiratory Journal (2023)

We are all blatantly aware of the devastating consequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and resulting coronavirus disease 2019 (COVID-19), which has accounted for over 6.6 million deaths and over 630 million recorded infections globally to date [1]. COVID-19 is predominantly characterised by respiratory symptoms ranging from mild cough and fever to severe acute respiratory distress syndrome and multiorgan failure [2–5]. The rapid design and implementation of effective vaccines across the globe has seen immense benefits in reducing the mortality rate [6], but vulnerable members of society are still very much at risk. Oxysterol metabolism offers an exciting novel angle to freshly consider when elucidating the molecular mechanisms underlying lung disease and lung infection. <https://bit.ly/3xnZx0C>
Active Surveillance for Low-risk Papillary Thyroid Carcinoma—Reply
Authors: Allen S. Ho, Wendy L. Sacks, Zachary S. Zumsteg
Journal: JAMA Oncology (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Inequities in surgical outcomes by race and sex in the United States: retrospective cohort study
Authors: Dan P Ly, Mariah B Blegen, Melinda M Gibbons, Keith C Norris, Yusuke Tsugawa
Journal: BMJ (2023)

To assess inequities in mortality by race and sex for eight common surgical procedures (elective and non-elective) across specialties in the United States.
Multiomics reveals multilevel control of renal and systemic metabolism by the renal tubular circadian clock
Authors: Yohan Bignon, Leonore Wigger, Camille Ansermet, Benjamin D. Weger, Sylviane Lagarrigue, Gabriel Centeno, Fanny Durussel, Lou Götz, Mark Ibberson, Sylvain Pradervand, Manfredo Quadroni, Meltem Weger, Francesca Amati, Frédéric Gachon, Dmitri Firsov
Journal: Journal of Clinical Investigation (2023)

Circadian rhythmicity in renal function suggests rhythmic adaptations in renal metabolism. To decipher the role of the circadian clock in renal metabolism, we studied diurnal changes in renal metabolic pathways using integrated transcriptomic, proteomic, and metabolomic analysis performed on control mice and mice with an inducible deletion of the circadian clock regulator Bmal1 in the renal tubule (cKOt). With this unique resource, we demonstrated that approximately 30% of RNAs, approximately 20% of proteins, and approximately 20% of metabolites are rhythmic in the kidneys of control mice. Several key metabolic pathways, including NAD+ biosynthesis, fatty acid transport, carnitine shuttle, and β-oxidation, displayed impairments in kidneys of cKOt mice, resulting in perturbed mitochondrial activity. Carnitine reabsorption from primary urine was one of the most affected processes with an approximately 50% reduction in plasma carnitine levels and a parallel systemic decrease in tissue carnitine content. This suggests that the circadian clock in the renal tubule controls both kidney and systemic physiology.
Abstract P4-01-12: BAT8006, a novel FRα ADC with strong bystander effect, for the treatment of advanced solid tumor
Authors: siqi mai, xingxing Mei, weijia Tang, Xin Zhou, Xuekang qi, Zhi Zhong, Shuoxu Li, Jianjun fan, Jirong Gan, Binghua Tan, Yao Qi, Yanling Guo, Shengfeng li, Jin-Chen Yu
Journal: Cancer Research (2023)

Abstract FRα is overexpressed in a number of cancers, including ovarian, breast, lung cancer, and endometrial carcinoma, yet limited expression in normal tissue. Efficacy of anti-FRα ADC have been demonstrated in clinical trials for high FRα expression ovarian cancer. These results validate FRα as a viable target for cancer treatment. We have developed a novel FRα ADC with strong bystander killing effect, BAT8006, which consists of a high-affinity antibody, an enzymatically cleavable linker and a topoisomerase I inhibitor as the payload, with DAR of 8. BAT8006 shows high affinity for the FRα antigen (KD &amp;lt; 0.5 nM) and FRα-expressing tumor cells. Upon binding to FRα on cell surface, BAT8006 internalizes effectively and traffics to the lysosome where payload is proteolytically released. BAT8006 demonstrated potent in vitro cell growth inhibitory activity to FRα-positive cells with IC50 values of ~ 1 nM. In an in vitro bystander killing assay, proliferation of FRα-negative cells was potently inhibited by addition of culture medium of BAT8006-treated FRα-positive cells, but not that of BAT8006-treated FRα-negative cells, indicating the bystander killing effect of the released payload in the culture medium. Less than 0.03% of the payload was released from BAT8006 when incubated with human or monkey plasma for 4 days in 37oC, suggesting the stability of BAT8006 in blood circulation. BAT8006 led to potent and dose-dependent tumor regression in patient-derived xenograft (PDX) model of SCLC. Furthermore, single dose of 2.5 mg/kg of BAT8006 showed complete eradication of tumor in choriocarcinoma JeG-3 xenograft mice model. In PDX of ovarian cancer, 2.5 mg/kg of BAT8006 (DAR8) demonstrated superior tumor inhibition activity than 5 mg/kg of BAT8006 with DAR4, suggesting the high DAR approach of BAT8006 would be more effective. In addition, BAT8006 showed favorable pharmacokinetic and safety profiles in cynomolgus monkeys with the highest non-severely toxic dose (HNSTD) of 30 mg/kg when dosed once every three weeks for 3 times. Together these results indicate that BAT8006 could potentially provide a therapeutic benefit to treat FRα-positive tumors including breast cancer in clinical trial. Citation Format: siqi mai, xingxing Mei, weijia Tang, Xin Zhou, Xuekang qi, Zhi Zhong, Shuoxu Li, Jianjun fan, Jirong Gan, Binghua Tan, Yao Qi, Yanling Guo, Shengfeng li, Jin-Chen Yu. BAT8006, a novel FRα ADC with strong bystander effect, for the treatment of advanced solid tumor [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-12.
Abstract P5-05-09: Multianalyte liquid biopsy to aid the diagnostic workup of breast cancer
Authors: Stephanie Shishido, Peter Kuhn, Jeremy Mason, James Hicks, Rafael Nevarez, Nicholas Matsumoto, Anand Kolatkar, Carmen Ruiz Velasco, Amanda Anderson, Michael Kidd, Kathy Wilkinson, E Shelley Hwang, Janice Lu, Jorge Nieva, Nikki Higa, Amin Naghdloo, Olivia Hart, Sonia Maryam Setayesh
Journal: Cancer Research (2023)

Abstract Breast cancer (BC) affects 1 in every 8 women in the United States and is currently the most prevalent cancer worldwide. Precise staging at diagnosis and prognosis are essential components for the clinical management of BC patients. The liquid biopsy (LBx) has promising applications in cancer screening and early diagnosis ultimately leading to better survival results and less disease burden. In this study, we evaluated the feasibility of the high-definition single cell assay (HDSCA) LBx platform to stratify disease states (early- and late-stage BC) and normal donors using peripheral blood samples. In the HDSCA3.0 workflow, both common white blood cells (WBCs) and rare cells, including circulating tumor cells (CTCs), EMT and platelet-coated cells, plus acellular structures are identified and classified computationally from scanned immunofluorescent images. This comprehensive LBx approach provides a quantitative landscape view of each individual case. In a striking example of the insight provided by HDSCA, we compared LBx results for early-stage and late-stage BC patients with two independent cohorts of normal donors to show the utility of a blood draw as a source of biomarkers for early-stage cancer detection. As expected, CTCs were detected at a higher level in late-stage patients, compared to either the early-stage or normal donors. Surprisingly, however, we observed a significantly higher incidence of tumor-associated large extracellular vesicles (LEVs) in the early-stage patients, compared to the other two groups. A patient-level classification model was able to correctly classifying LBx profiles as normal, early, or late with LEV enumeration as the strongest predictor, followed by epi.CTC enumeration. We will present a reproducible LBx profile of rare cells and LEVs of early-stage disease compared to late-stage BC and normal donors with high accuracy, allowing for robust stratification. Our findings illustrate the feasibility of the LBx to assess early disease states prior to clinically defined metastasis, stratified from normal donors, highlighting the general consideration of the liquid biopsy for the diagnostic work-up and potentially screening. Citation Format: Stephanie Shishido, Peter Kuhn, Jeremy Mason, James Hicks, Rafael Nevarez, Nicholas Matsumoto, Anand Kolatkar, Carmen Ruiz Velasco, Amanda Anderson, Michael Kidd, Kathy Wilkinson, E Shelley Hwang, Janice Lu, Jorge Nieva, Nikki Higa, Amin Naghdloo, Olivia Hart, Sonia Maryam Setayesh. Multianalyte liquid biopsy to aid the diagnostic workup of breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-05-09.